The following is offered as background information only and is not admitted to be prior art to the present invention.
Solids, including pharmaceuticals, often have more than one crystal form, and this is known as polymorphism. Polymorphism occurs when a compound crystallizes in a multiplicity of solid phases that differ in crystal packing. Numerous examples are cited in the standard references of solid state properties of pharmaceuticals, Byrn, S. R., Solid-State Chemistry of Drugs, New Your, Academic Press (1982); Kuhnert-Brandstatter, M., Thermomiscroscopy In The Analysis of Pharmaceuticals, New York, Pergamon Press (1971) and Haleblian, J. K. and McCrone, W. Pharmaceutical applications of polymorphism. J. Pharm. Sci., 58, 911 (1969). Byrn states that, in general, polymorphs exhibit different physical characteristics including solubility and physical and chemical stability.
Because of differences in molecular packing, polymorphs may differ in ways that influence drug release, solid-state stability, and pharmaceutical manufacturing. The relative stability and the interconversions of polymorphs are particularly important to the selection of a marketed drug. A suitable polymorph may hinge upon the issue of physical stability. For example, the selection of a marketed drug may depend upon the availability and selection of a suitable polymorph having desirable characteristics, such as excellent physical stability or the ability to be manufactured in large scale. The performance of the solid dosage form should not be limited by polymorphic transformations during the shelf life of the product. It is important to note that there is no reliable method to predict the observable crystal structures of a given drug or to predict the existence of polymorphs with desirable physical properties.
PKs are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine, and threonine residues of proteins. The consequences of this seemingly simple activity are staggering since virtually all aspects of cell life (e.g., cell growth, differentiation, and proliferation) in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
Receptor tyrosine kinases (RTKs), a class of PK, are excellent candidates for molecular targeted therapy, because they play key roles in controlling cell proliferation and survival and are frequently dysregulated in a variety of malignancies. The mechanisms of dysregulation include overexpression (Her2/neu in breast cancer, epidermal growth factor receptor in non-small cell lung cancer), activating mutations (KIT in gastrointestinal stromal tumors, fms-related tyrosine kinase 3/Flk2 (FLT3) in acute myelogenous leukemia), and autocrine loops of activation (vascular endothelial growth factor/VEGF receptor (VEGF/VEGFR) in melanoma, platelet-derived growth factor/PDGF receptor (PDGF/PDGFR) in sarcoma).
Aberrantly regulated RTKs have been described in comparable human and canine cancers. For example, aberrant expression of the Met oncogene occurs in both human and canine osteosarcoma. Interestingly, comparable activating mutations in the juxtamembrane (JM) domain of c-kit are seen in 50-90% of human gastrointestinal stromal tumors (GISTs) and in 30-50% of advanced canine MCTs (mast cell tumors). Although the mutations in human GISTs consist of deletions in the JM domain and those in canine MCTs consist of internal tandem duplications (ITDs) in the JM domain, both lead to constitutive phosphorylation of KIT in the absence of ligand binding. The RTKs and their ligands, VEGF, PDGF, and FGF mediate neo-vascularization, known as angiogenesis, in solid tumors. Consequently, by inhibiting the RTKs, the growth of new blood vessels into tumors may be inhibited.
Antiangiogenesis agents, a class of molecules that inhibits the growth of blood vessels into tumors, have much less toxicity to the body compared to conventional anti-cancer drugs. U.S. Pat. No. 6,573,293, incorporated herein by reference, discloses, among other compounds, 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (hereinafter “Compound I”). It has the following structure:

Compound I is a small molecule that exhibits PK modulating ability. The compound is therefore useful in treating disorders related to abnormal PK activity. It is an inhibitor of the RTKs, PDGFR, VEGFR, KIT, and FLT3. Compound I has been shown to inhibit KIT phosphorylation, arrest cell proliferation, and induce cell cycle arrest and apoptosis in malignant mast cell lines in vitro expressing various forms of mutant KIT. Compound I and related molecules are effective in preclinical models against tumor xenografts arising from cell lines of diverse human tumor origin.
Compound I is useful for treating cancers in companion animals, mainly dogs, and is also useful for the treatment of, inter alia, cancer in humans. Such cancers include, but are not limited to, leukemia, brain cancer, non-small cell lung cancer, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, small-cell lung cancer, glioma, colorectal cancer, genitourinary cancer, and gastrointestinal stromal cancer. Also, Compound I is useful for the treatment of diseases related to overexpression of mast cells, including but not limited to, mastocytosis in humans and mast cell tumors in dogs.
Compound I was recently shown to be clinically effective against a number of spontaneous malignancies in dogs. In the study, 11 of 22 canine MCTs showed durable objective responses (partial responses and complete responses) to Compound I treatment; 9 of these MCTs possessed ITDs in the JM domain of c-kit.
Compound I readily crystallizes. Its solubility is about 10 μg/mL in pH 6 phosphate buffer at 25° C. When the compound was synthesized, very fine particles precipitated out of solution during the last step of synthesis. Subsequent isolation of these fine particles by filtration was slow, and a hard cake resulted after filtration. There is a need for a salt of Compound I which has physical stability and desirable physical properties.